The head-to-tail coupling of isopentenyl pyrophosphate with dimethylallyl pyrophosphate and geranyl pyrophosphate is a key bond-forming reaction in the sterol biosynthetic pathway. This proposal is concerned with the topology of the substrates in the enzyme-substrate complex. We plan to synthesize a novel class of analogues for farnesyl pyrophosphate synthetase. These are single molecules which covalently link the homoallylic and allylic substrates thereby restricting the topologies of the partners to a narrow range of reactive conformations. From a study of the ability of these analogues to function as alternate substrates and inhibitors, it will be possible to deduce the topology of the bound substrates. We believe that the structural information will provide important clues about the catalytic process, in particular the nature of the base which assists proton removal in the final step of the condensation reaction. We also plan to use the bisubstrate analogues in a series of non-enzymatic model studies to see if current ideas about the role of the enzyme in the catalytic process are on a firm chemical footing.